Morphine, which is derived from opium, the dried milky exudate of unripe poppy capsules (Papaver somniferum), has been used in the form of its hydrochloride as an agent against severe pain since its isolation by Serturner (1806). When this analgesic is used frequently and over a long period of time, for example in tumor patients, there is a risk of addiction and the development of tolerance (morphinism).
The side effects observed during correct use, such as euphoric effect, emetic effect, spastic constipation and increase in smooth muscle tone, also reduce the therapeutic effectiveness of morphine.
Therefore, there has been no lack of attempts to synthesize strongly acting, but side effect-free analgesics. Although the partially-synthetic product diamorphine (heroin) is 10 times more effective than morphine, it is more addictive than morphine. Pethidine is about 5 times less effective than morphine and is also less spasmogenic.
Pentazocine and buprenorphine are subject to narcotics legislation because of their potential of causing addiction.
Tramadol is not yet known to present a potential of causing addiction, but it is only about 1/10-1/5 as effective as morphine.
There thus remains a great need for a reliable analgesic medication that is highly effective against severe pain with few side effects and which presents no potential for causing addiction.
It has been proposed to use a combination of active substances to reduce the use of analgesics, or to enhance their inadequate analgesic effect. These attempts have aimed at making the side effects of morphine less pronounced and enhancing its analgesic effect by combining it with selected analgesics.
For example, since morphine has no anti-inflammatory effect, this deficiency in the effectiveness of morphine can be overcome by combining it with anti-inflammatory or antipyretic analgesics. Thus, for instance, Vergoni et al. (Life Sci., 50(16), page 135-138 (1992)) describe the potentiating effects of pinacidil on the analgesic effect of morphine. A combination of rectally administered indomethacin with intravenously administered morphine is described by Segstro and Morley-Forster in Can. J. Anaesth. 38(5), 578-581 (1991).
Animal experiments which describe the potentiation of analgesic effects of morphine and clonidine in rats were reported by Wilcox, Carlsson, Jochim and Jurna in Brain Res. 405(1), 84-93 (1987).
All experiments are aimed at enhancing the analgesic effects in the sense of a synergistic effect in order to reduce the dose of analgesic or anti-inflammatory agent and morphine.
Flupirtin (INN) is an analgesic with muscle-relaxing components of action. (B. Nickel, V. Jakovlev, I. Szelenyi, Arzneim.--Forsch. 40(II)8, 909-911 (1990) German published patent 36 01 195).
It has no dependence potential (B. Nickel, H. O. Barbe, I. Szelenyi, Arzneim.--Forsch. 40(II)8, 905-908 (1990)). The antinociceptive effect of flupirtin cannot be antagonized by naloxon. Flupirtin also shows no affinity for opiate receptors. (B. Nickel, A. Herz, V. Jakovlev, U. Tibes, Arzneim.--Forsch. 35(II), 1402 (1985)).